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EP0316704A2 - Fluorocytidine derivatives, their preparation and medical preparations containing them - Google Patents

Fluorocytidine derivatives, their preparation and medical preparations containing them Download PDF

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Publication number
EP0316704A2
EP0316704A2 EP88118515A EP88118515A EP0316704A2 EP 0316704 A2 EP0316704 A2 EP 0316704A2 EP 88118515 A EP88118515 A EP 88118515A EP 88118515 A EP88118515 A EP 88118515A EP 0316704 A2 EP0316704 A2 EP 0316704A2
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EP
European Patent Office
Prior art keywords
deoxy
fluoro
fluorocytidine
cytidine
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP88118515A
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German (de)
French (fr)
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EP0316704A3 (en
EP0316704B1 (en
Inventor
Morio Fujiu
Hideo Ishitsuka
Masanori Miwa
Isao Imperial Higashihakuraku Umeda
Kazuteru Yokose
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to EP88118515A priority Critical patent/EP0316704B1/en
Publication of EP0316704A2 publication Critical patent/EP0316704A2/en
Publication of EP0316704A3 publication Critical patent/EP0316704A3/en
Application granted granted Critical
Publication of EP0316704B1 publication Critical patent/EP0316704B1/en
Priority to NL300045C priority patent/NL300045I2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to new 5'-deoxy-5-fluorocytidine derivatives, a process for the preparation thereof and antitumor agents based on these derivatives.
  • R1, R2 and R3 independently of one another are hydrogen or a group which can be easily split off under physiological conditions, with the condition that at least one of R1, R2 and R3 is a group which can be easily split off under physiological conditions, and hydrates or solvates of the compounds of the general formula I.
  • Groups which can easily be split off under physiological conditions are preferably groups of the formula R4CO-, R5OCO- or R6SCO-, in which R4 are hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl and R5 and R6 are alkyl or aralkyl.
  • R4 are hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl and R5 and R6 are alkyl or aralkyl.
  • alkyl denotes a straight-chain or branched chain with 1-19 C atoms, e.g.
  • Cycloalkyl means e.g.
  • "Oxoalkyl” denotes e.g. Acetyl, propionyl, butyryl, 2-oxopropyl or 3-oxobutyl.
  • Alkenyl denotes optionally substituted alkenyl with 3-19 C atoms, such as allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptadecenyl, heptadecadienyl, Heptadecatrienyl, nonadecenyl, nonadecadienyl, nonadecatetraenyl or 2-phenylvinyl.
  • Aralkyl means optionally substituted aralkyl, such as benzyl, 1-phenylethyl, methyl, fluorine, chlorine, methoxy, dimethoxy or nitrobenzyl, phenethyl, picolyl or 3-indolylmethyl.
  • Aryl denotes optionally substituted aryl, such as phenyl, tolyl, xylyl, mesityl, cumenyl, ethyl, fluorine, chlorine, bromine, iodine, difluoro, dichloro, methoxy, dimethoxy, trimethoxy, ethoxy -, diethoxy-, triethoxy-, propoxy-, methylenedioxy-, methylthio-, nitro-, cyano-, acetyl- or carbamoylphenyl, methoxycarbonylphenyl, naphthyl, biphenylyl, thienyl, methylthienyl, furyl, nitrofuryl, pyrrolyl, methylpyrrolyl, pyazololylyl, imidazolylylzrazyl Pyridyl, methylpyridyl or pyrazinyl.
  • aryl such as phenyl, to
  • Particularly preferred compounds of formula I are the following: N4-acetyl-5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluoro-N4-propionylcytidine, N4-butyryl-5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluoro-N4-isobutyrylcytidine, 5′-deoxy-5-fluoro-N4- (2-methylbutyryl) cytidine, 5′-deoxy-N4- (2-ethylbutyryl) -5-fluorocytidine, 5′-deoxy-N4- (3,3-dimethylbutyryl) -5-fluorocytidine, 5′-deoxy-5-fluoro-N4-pivaloylcytidine, 5′-deoxy-5-fluoro-N4-valerylcytidine, 5′-deoxy-5-fluoro-N4-isovalerylcytidine
  • the compounds of formula I and the hydrates and solvates thereof can be prepared by using a compound of the general formula wherein R7 is hydrogen or an amino protecting group, R8 and R9 are independently hydrogen or a hydroxy protecting group or R8 and R9 together are a cyclic hydroxy protecting group, with a compound of the general formula XCOR4, wherein X is a leaving group and R4 is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, Aralkyl or aryl, or with a compound of the general formula YCOR10, wherein Y is halogen and R10 is a group of the formula R5O- or R6S-, in which R5 and R6 are alkyl or aralkyl, and an existing protective group is split off.
  • amino protecting groups are benzyloxycarbonyl, phenoxycarbonyl, 2,2-trichloroethoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and trifluoroacetyl.
  • hydroxyl protective groups are benzyl, methoxybenzyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy) methyl and tetrahydropyranyl.
  • cyclic hydroxyl protective groups are cyclic acetals, ketals, carbonates or orthoesters or cyclic 1,3- (1,1,3,3-tetraisopropyl) disiloxane diyl derivatives.
  • leaving groups are halogens, acyloxy, alkyloxycarbonyloxy, succinimidoxy, phthalimidoxy, 4-nitrophenyl, azido, 2,4,6-triisopropylbenzenesulfonyl and diethoxyphosphoryloxy.
  • Halogen means chlorine, bromine or iodine.
  • 5'-Deoxy-5-fluorocytidine is known from the compounds of the formula II [J. Med. Chem., 22 , (1979) 1330].
  • the other compounds of the formula II can be prepared in a manner known per se [Chem. Pharm. Bull., 33 , (1985) 2575] starting from 5'-deoxy-5-fluorocytidine or from 5'-deoxy-5-fluorouridine.
  • the compounds of the formula XCOR4 used in the above process are acid halides, acid anhydrides, mixed anhydrides (prepared by reaction of R4COOH with 2,4,6-triisopropylbenzenesulfonyl chloride or diethyl chlorophosphate, in which R4 has the above meaning) activated esters, such as N-hydroxysuccinimide esters, N- Hydroxyphthalimide ester or 4-nitrophenyl ester; Acylazide or mixed carboxylic acid anhydrides.
  • the compounds of formula YCOR10 are alkoxycarbonyl halides, aralkoxycarbonyl halides, alkyl thiocarbonyl halides or aralkyl thiocarbonyl halides.
  • the reaction of a compound of formula II with a compound of formula XCOR4 or YCOR10 can be carried out in a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, methanol, ethanol or water or mixtures thereof, in the presence of an acid acceptor, such as Triethylamine, pyridine, picoline, dimethylaminopyridine, lutidine, N, N-dimethylaniline or an alkali metal hydroxide, carbonate or phosphate.
  • the reaction can be carried out over a wide temperature range However, expediently between about 0 and 120 ° C, preferably between 0 and 50 ° C. For 1 mole of a compound of formula II 1, 2 or 3 moles or an excess of a compound of formula XCOR4 or YCOR10 are used.
  • a protective group can be split off in a manner known per se.
  • the compounds of the present invention can be isolated and purified in a manner known per se, e.g. by evaporation, filtration, extraction, waste, chromatography and / or recrystallization.
  • the compounds of formula I can exist as solvates, in particular as hydrates.
  • the hydrogenation can take place during production or as a result of the hygroscopic properties of an originally anhydrous product.
  • a completely or partially anhydrous product e.g. exposed to a humid atmosphere at around 10 to 40 ° C.
  • Solvates with pharmaceutically acceptable solvents such as ethanol can e.g. arise during crystallization.
  • the compounds of the formula I and the hydrates and solvates thereof are both orally and parenterally active against Sarcoma 180, Meth A fibrosarcoma and Lewis lung carcinoma in mice over a wide dosage range and can be used as antitumor agents.
  • 5-Fluorouracil and its derivatives have the disadvantage of intestinal and immunosuppressive toxicity, which drastically limits their use.
  • the present compounds of formula I are much less toxic in the intestinal tract and to the immune system than 5-fluorouracil (JACS 79, 1957, 4559) and the precursors thereof, such as tegafur: uracil, 1: 4 (UFT) and 5 'Deoxy-5-fluorouridine (US 4071680).
  • the compounds of formula I can therefore be used in the treatment of various tumors in humans.
  • the invention also relates to pharmaceutical preparations which contain one or more compounds of the formula I and the use of these compounds for the production of medicaments for the treatment of tumors.
  • the compounds of formula I can be administered orally or non-orally to humans, optionally with the addition of a compatible carrier material.
  • a compatible carrier material can be an organic or inorganic inert substance suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils or polyalkylene glycols.
  • the pharmaceutical preparations can be in solid form as tablets, dragees, granules, capsules, suppositories or as enterally administrable tablets, granules or capsules; are in semi-solid form as ointments or in liquid form as solutions, suspensions or emulsions.
  • auxiliaries such as preservatives or stabilizers, emulsifiers, fragrances, salts for changing the osmotic pressure or buffers. They can be produced in a manner known per se.
  • the compounds of the formula I can be used individually or as mixtures of two or more, the active ingredient content being in the range from about 0.1 to 99.5%, preferably 0.5 to 95%, of the total weight of the preparation.
  • the preparations can also contain other pharmaceutically active substances.
  • the daily dose of the compounds of formula I depends on the weight of the patient and the disease to be treated, but is generally in the range from 0.5 to 700, preferably from about 3 to 500 mg / kg body weight.
  • the antitumor activity of the compounds of the formula I is illustrated in the following experiments:
  • Meth A Fibrosarcoma cells (2 x 105 cells) are implanted subcutaneously in mice (21-22 g). The test against Meth A fibrosarcoma and the determination of the inhibition of tumor growth was carried out in a similar manner to the test against Sarcoma 180. The results are shown in Table 2.
  • the antitumor activity of the compound of Example 3 was compared to that of 5'-deoxy-5-fluorouridine.
  • the results are shown in Table 3.
  • the faeces were observed on day 8 of the experiment.
  • the results show that the compound of Example 3 has higher anti-tumor activity and lower toxicity than 5'-deoxy-5-fluorouridine.
  • the compound of Example 3 did not cause diarrhea, the latter being the dose limiting factor of 5'-deoxy-5-fluorouridine.
  • the antitumor activity of the compound of the present example 1 was compared with that of 5'-deoxy-5-fluorouridine and the combination preparation, UFT (Tegafur: uracil, 1: 4).
  • Mice were subcutaneously inoculated with Lewis lung carcinoma (10 0 cells) on day 0. The compounds were administered orally 14 times a day from day 1.
  • the effective dose (ED50) at which tumor growth was inhibited by 50% and the toxic doses were determined.
  • the therapeutic index (toxic dose / ED50) are given in Table 4. The results show that the compound of Example 1 has a higher therapeutic index than the classic precursors of 5-fluorouracil, 5'-deoxy-5-fluorouridine and UFT.
  • the antitumor activity of the compound of Example 1 was compared in three murine tumor models with that of 5'-deoxy-5-fluorouridine and 5'-deoxy-5-fluorocytidine.
  • Mice were inoculated subcutaneously on day 0 with Sarcoma 180, Meth A Fibrosarcoma and UV 2237 Fibrosarcoma. From day 1, the test substances were administered orally to the mice 7 times. Efficacy was measured as a therapeutic index (ED max / ED50) on day 14 after tumor inoculation. ED max is the dose at which tumor growth is maximally inhibited. The results are shown in Table 5.
  • the acute toxicity (LD50) of the compounds of the present examples 1, 5, 9, 24, 34, 46 and 47 is more than 2000 mg / kg when administered orally to mice.
  • Example 4 (b) The product of Example 4 (a) is treated in analogy to Example 1 (b). Colorless crystals of N4-butyryl-5'-deoxy-5-fluorocytidine are obtained.
  • Example 58 (a) The product of Example 58 (a) is treated in analogy to Example 1 (b). Amorphous 5'-deoxy-5-fluoro-N4-formylctidin ⁇ MS 274 (MH+) is obtained.
  • Gelatin capsules of the following composition are produced in a manner known per se: N4-butyryl-5'-deoxy-5-fluorocytidine 100 mg Cornstarch 20 mg Titanium dioxide 385 mg Magnesium stearate 5 mg Movie 20 mg PEG 6000 3 mg Talk 10 mg total weight 543 mg
  • a sterile aqueous solvent such as water for injection or isotonic sodium chloride solution or 5% dextrose ⁇ for parenteral administration is added to the above dry dosage forms.

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Abstract

derivs. of formula (I), their hydrates and solvates are new. In (I) R1, R2 and R3 = H or a gp. which is easily removed under physiological conditions, at least one of them being other than H. Specifically easily hydrolysed gps. are of formulae R4CO, R5O.CO or R6S.CO; R4 = H, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl; R5 and R6 = alkyl or aralkyl.

Description

Die vorliegende Erfindung betrifft neue 5′-Deoxy-5-fluor­cytidinderivate, ein Verfahren zur Herstellung davon und Antitumormittel auf der Basis dieser Derivate.The present invention relates to new 5'-deoxy-5-fluorocytidine derivatives, a process for the preparation thereof and antitumor agents based on these derivatives.

Letztere haben die allgemeine Formel

Figure imgb0001
worin R¹, R² und R³ unabhängig voneinander Wasser­stoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe sind, mit der Bedingung, dass zumindest eines von R¹, R² und R³ eine unter physiologischen Bedingungen leicht abspaltbare Gruppe ist, sowie Hydrate oder Solvate der Verbindungen der allgemeinen Formel I.The latter have the general formula
Figure imgb0001
 wherein R¹, R² and R³ independently of one another are hydrogen or a group which can be easily split off under physiological conditions, with the condition that at least one of R¹, R² and R³ is a group which can be easily split off under physiological conditions, and hydrates or solvates of the compounds of the general formula I.

"Unter physiologischen Bedingungen leicht abspaltbare Gruppen" sind vorzugsweise Gruppen der Formel R⁴CO-, R⁵OCO- oder R⁶SCO-, worin R⁴ Wasserstoff, Alkyl, Cyclo­alkyl, Oxoalkyl, Alkenyl, Aralkyl oder Aryl und R⁵ und R⁶ Alkyl oder Aralkyl sind. Im Rahmen der vorliegenden Erfindung bezeichnet "Alkyl" eine geradkettige oder verzweigte Kette mit 1-19 C-Atomen, z.B. Methyl, Aethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl, t-Butyl, Pentyl, Isopentyl, Neopentyl, Hexyl, Isohexyl, Heptyl, Octyl, Nonyl, Decyl, Undecyl, Dodecyl, Tridecyl, Tetradecyl, Pentadecyl, Hexa­decyl, Heptadecyl oder Nonadecyl. "Cycloalkyl" bedeutet z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder Adamantyl. "Oxoalkyl" bezeichnet z.B. Acetyl, Propionyl, Butyryl, 2-Oxopropyl oder 3-Oxobutyl. "Alkenyl" bezeichnet gegebenenfalls substituiertes Alkenyl mit 3-19 C-Atome, wie Allyl, Butenyl, 3-Methyl-2-butenyl, 1-Methyl-2-propenyl, Hexenyl, Decenyl, Undecenyl, Tridecenyl, Pentadecenyl, Hepta­decenyl, Heptadecadienyl, Heptadecatrienyl, Nonadecenyl, Nonadecadienyl, Nonadecatetraenyl oder 2-Phenylvinyl. "Aralkyl" bedeutet gegebenenfalls substituiertes Aralkyl, wie Benzyl, 1-Phenyläthyl, Methyl-, Fluor-, Chlor-, Methoxy-, Dimethoxy- oder Nitrobenzyl, Phenäthyl, Picolyl oder 3-Indolylmethyl. "Aryl" bezeichnet gegebenenfalls substi­tuiertes Aryl, wie Phenyl, Tolyl, Xylyl, Mesityl, Cumenyl, Aethyl-, Fluor-, Chlor-, Brom-, Jod-, Difluor-, Dichlor-, Methoxy-, Dimethoxy-, Trimethoxy-, Aethoxy-, Diäthoxy-, Triäthoxy-, Propoxy-, Methylendioxy-, Methylthio-, Nitro-, Cyan-, Acetyl- oder Carbamoylphenyl, Methoxycarbonylphenyl, Naphthyl, Biphenylyl, Thienyl, Methylthienyl, Furyl, Nitro­furyl, Pyrrolyl, Methylpyrrolyl, Imidazolyl, Pyrazolyl, Pyridyl, Methylpyridyl oder Pyrazinyl."Groups which can easily be split off under physiological conditions" are preferably groups of the formula R⁴CO-, R⁵OCO- or R⁶SCO-, in which R⁴ are hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl and R⁵ and R⁶ are alkyl or aralkyl. In the context of the present invention, "alkyl" denotes a straight-chain or branched chain with 1-19 C atoms, e.g. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl , Heptadecyl or nonadecyl. "Cycloalkyl" means e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl. "Oxoalkyl" denotes e.g. Acetyl, propionyl, butyryl, 2-oxopropyl or 3-oxobutyl. "Alkenyl" denotes optionally substituted alkenyl with 3-19 C atoms, such as allyl, butenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, hexenyl, decenyl, undecenyl, tridecenyl, pentadecenyl, heptadecenyl, heptadecadienyl, Heptadecatrienyl, nonadecenyl, nonadecadienyl, nonadecatetraenyl or 2-phenylvinyl. "Aralkyl" means optionally substituted aralkyl, such as benzyl, 1-phenylethyl, methyl, fluorine, chlorine, methoxy, dimethoxy or nitrobenzyl, phenethyl, picolyl or 3-indolylmethyl. "Aryl" denotes optionally substituted aryl, such as phenyl, tolyl, xylyl, mesityl, cumenyl, ethyl, fluorine, chlorine, bromine, iodine, difluoro, dichloro, methoxy, dimethoxy, trimethoxy, ethoxy -, diethoxy-, triethoxy-, propoxy-, methylenedioxy-, methylthio-, nitro-, cyano-, acetyl- or carbamoylphenyl, methoxycarbonylphenyl, naphthyl, biphenylyl, thienyl, methylthienyl, furyl, nitrofuryl, pyrrolyl, methylpyrrolyl, pyazololylyl, imidazolylylzrazyl Pyridyl, methylpyridyl or pyrazinyl.

Besonders bevorzugte Verbindungen der Formel I sind die folgenden:

N⁴-Acetyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-propionylcytidin,
N⁴-Butyryl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-isobutyrylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylbutyryl)cytidin,
5′-Deoxy-N⁴-(2-äthylbutyryl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,3-dimethylbutyryl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-pivaloylcytidin,
5′-Deoxy-5-fluor-N⁴-valerylcytidin,
5′-Deoxy-5-fluor-N⁴-isovalerylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-hexanoylcytidin,
5′-Deoxy-5-fluor-N⁴-heptanoylcytidin,
5′-Deoxy-5-fluor-N⁴-octanoylcytidin,
5′-Deoxy-5-fluor-N⁴-nonanoylcytidin,
5′-Deoxy-5-fluor-N⁴-hexadecanoylcytidin,
N⁴-Benzoyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-methylbenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-methylbenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylbenzoyl)cytidin,
5′-Deoxy-N⁴-(4-äthylbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,4-dimethylbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dimethylbenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(3,4-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(3,4,5-trimethoxybenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3,4,5-triäthoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(4-äthoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-propoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(3,5-diäthoxybenzoyl)-5-fluorcytidin,
N⁴-(4-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-N⁴-(3,4-dichlorbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dichlorbenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-nitrobenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxycarbonylbenzoyl)cytidin,
N⁴-(4-Acetylbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(phenylacetyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxyphenylacetyl)cytidin,
5′-Deoxy-5-fluor-N⁴-nicotinoylcytidin,
5′-Deoxy-5-fluor-N⁴-isonicotinoylcytidin,
5′-Deoxy-5-fluor-N⁴-picolinoylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(5-nitro-2-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(2-thenoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(5-methyl-2-thenoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(1-methyl-2-pyrrolcarbonyl)­cytidin,
5′-Deoxy-5-fluor-N⁴-(3-indolylacetyl)cytidin,
N⁴-(3-Butenoyl)-5′-deoxy-5-fluorcytidin,
3′-O-Benzoyl-5′-deoxy-5-fluorcytidin,
N⁴, 3′-O-Dibenzoyl-5′-deoxy-5-fluorcytidin und
5′-Deoxy-N⁴-(äthylthio)carbonyl-5-fluorcytidin.
Particularly preferred compounds of formula I are the following:

N⁴-acetyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-propionylcytidine,
N⁴-butyryl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-isobutyrylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylbutyryl) cytidine,
5′-deoxy-N⁴- (2-ethylbutyryl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,3-dimethylbutyryl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-pivaloylcytidine,
5′-deoxy-5-fluoro-N⁴-valerylcytidine,
5′-deoxy-5-fluoro-N⁴-isovalerylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴-hexanoylcytidine,
5′-deoxy-5-fluoro-N⁴-heptanoylcytidine,
5′-deoxy-5-fluoro-N⁴-octanoylcytidine,
5′-deoxy-5-fluoro-N⁴-nonanoylcytidine,
5′-deoxy-5-fluoro-N⁴-hexadecanoylcytidine,
N⁴-benzoyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-methylbenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-methylbenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylbenzoyl) cytidine,
5′-deoxy-N⁴- (4-ethylbenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,4-dimethylbenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dimethylbenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxybenzoyl) cytidine,
5′-deoxy-N⁴- (3,4-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (3,4,5-trimethoxybenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3,4,5-triethoxybenzoyl) cytidine,
5′-deoxy-N⁴- (4-ethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-propoxybenzoyl) cytidine,
5′-deoxy-N⁴- (3,5-diethoxybenzoyl) -5-fluorocytidine,
N⁴- (4-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-N⁴- (3,4-dichlorobenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dichlorobenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-nitrobenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxycarbonylbenzoyl) cytidine,
N⁴- (4-acetylbenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (phenylacetyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxyphenylacetyl) cytidine,
5′-deoxy-5-fluoro-N⁴-nicotinoylcytidine,
5′-deoxy-5-fluoro-N⁴-isonicotinoylcytidine,
5′-deoxy-5-fluoro-N⁴-picolinoylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (5-nitro-2-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (2-thenoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (5-methyl-2-thenoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (1-methyl-2-pyrrolcarbonyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-indolylacetyl) cytidine,
N⁴- (3-butenoyl) -5′-deoxy-5-fluorocytidine,
3′-O-benzoyl-5′-deoxy-5-fluorocytidine,
N⁴, 3′-O-dibenzoyl-5′-deoxy-5-fluorocytidine and
5'-deoxy-N⁴- (ethylthio) carbonyl-5-fluorocytidine.

Weitere bevorzugte Verbindungen der Formel I sind die folgenden:

5′-Deoxy-5-fluor-N⁴-octadecanoylcytidin,
N⁴-Cyclopropancarbonyl-5′-deoxy-5-fluorcytidin,
N⁴-Cyclohexancarbonyl-5′-deoxy-5-fluorcytidin,
N⁴-(1-Adamantancarbonyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(2,4-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-piperonyloylcytidin,
5′-Deoxy-5-fluor-N⁴-(4-fluorbenzoyl)cytidin,
N⁴-(2-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
N⁴-(3-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(3-nitrobenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-[4-(methylthio)benzoyl]cytidin,
5′-Deoxy-5-fluor-N⁴-(2-naphthoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-phenylpropionyl)cytidin,
N⁴-Cinnamoyl-5′-deoxy-5-fluorcytidin,
2′,3′-di-O-Benzoyl-5′-deoxy-5-fluorcytidin,
N⁴,2′-0,3′-O-Tribenzoyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(octyloxycarbonyl)cytidin,
N⁴-(Benzyloxycarbonyl)-5′-deoxy-5-fluorcytidin und
5′-Deoxy-5-fluor-N⁴-formylcytidin.
Further preferred compounds of formula I are the following:

5′-deoxy-5-fluoro-N⁴-octadecanoylcytidine,
N⁴-cyclopropanecarbonyl-5'-deoxy-5-fluorocytidine,
N⁴-cyclohexanecarbonyl-5'-deoxy-5-fluorocytidine,
N⁴- (1-adamantane carbonyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (2-methoxybenzoyl) cytidine,
5′-deoxy-N⁴- (2,4-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-piperonyloylcytidine,
5′-deoxy-5-fluoro-N⁴- (4-fluorobenzoyl) cytidine,
N⁴- (2-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
N⁴- (3-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (3-nitrobenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- [4- (methylthio) benzoyl] cytidine,
5′-deoxy-5-fluoro-N⁴- (2-naphthoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-phenylpropionyl) cytidine,
N⁴-cinnamoyl-5′-deoxy-5-fluorocytidine,
2 ′, 3′-di-O-benzoyl-5′-deoxy-5-fluorocytidine,
N⁴, 2′-0.3′-O-tribenzoyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (octyloxycarbonyl) cytidine,
N⁴- (benzyloxycarbonyl) -5'-deoxy-5-fluorocytidine and
5'-deoxy-5-fluoro-N⁴-formylcytidine.

Die Verbindungen der Formel I und die Hydrate und Solvate davon können dadurch hergestellt werden, dass man eine Ver­bindung der allgemeinen Formel

Figure imgb0002
worin R⁷ Wasserstoff oder eine Aminoschutzgruppe, R⁸ und R⁹ unabhängig voneinander Wasserstoff oder eine Hydroxyschutzgruppe oder R⁸ und R⁹ zusammen eine cyclische Hydroxyschutzgruppe sind, mit einer Verbindung der allgemeinen Formel XCOR⁴, worin X eine Abgangsgruppe und R⁴ Wasserstoff, Alkyl, Cycloalkyl, Oxoalkyl, Alkenyl, Aralkyl oder Aryl ist, oder mit einer Verbindung der allgemeinen Formel YCOR¹⁰, worin Y Halogen und R¹⁰ eine Gruppe der Formel R⁵O- oder R⁶S-, in der R⁵ und R⁶ Alkyl oder Aralkyl sind, umsetzt und eine vorhandene Schutzgruppe abspaltet.The compounds of formula I and the hydrates and solvates thereof can be prepared by using a compound of the general formula
Figure imgb0002
 wherein R⁷ is hydrogen or an amino protecting group, R⁸ and R⁹ are independently hydrogen or a hydroxy protecting group or R⁸ and R⁹ together are a cyclic hydroxy protecting group, with a compound of the general formula XCOR⁴, wherein X is a leaving group and R⁴ is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, Aralkyl or aryl, or with a compound of the general formula YCOR¹⁰, wherein Y is halogen and R¹⁰ is a group of the formula R⁵O- or R⁶S-, in which R⁵ and R⁶ are alkyl or aralkyl, and an existing protective group is split off.

Beispiele von Aminoschutzgruppen sind Benzyloxycarbonyl, Phenoxycarbonyl, 2,2-Trichloräthoxycarbonyl, Aethoxycarbonyl, t-Butoxycarbonyl und Trifluoracetyl. Beispiele von Hydroxy­schutzgruppen sind Benzyl, Methoxybenzyl, Trimethylsilyl, Triäthylsilyl, Isopropyldimethylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Thexyldimethylsilyl, Allyl, Methoxy­methyl, (2-Methoxyäthoxy)methyl und Tetrahydropyranyl. Beispiele von cyclischen Hydroxyschutzgruppen sind cyclische Acetale, Ketale, Carbonate oder Orthoester oder cyclische 1,3-(1,1,3,3-Tetraisopropyl)disiloxandiyl-Derivate. Beispiele von Abgangsgruppen sind Halogene, Acyloxy, Alkyloxycarbonyl­oxy, Succinimidoxy, Phthalimidoxy, 4-Nitrophenyl, Azido, 2,4,6-Triisopropylbenzolsulfonyl und Diäthoxyphosphoryloxy. "Halogen" bezeichnet Chlor, Brom oder Jod.Examples of amino protecting groups are benzyloxycarbonyl, phenoxycarbonyl, 2,2-trichloroethoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and trifluoroacetyl. Examples of hydroxyl protective groups are benzyl, methoxybenzyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy) methyl and tetrahydropyranyl. Examples of cyclic hydroxyl protective groups are cyclic acetals, ketals, carbonates or orthoesters or cyclic 1,3- (1,1,3,3-tetraisopropyl) disiloxane diyl derivatives. Examples of leaving groups are halogens, acyloxy, alkyloxycarbonyloxy, succinimidoxy, phthalimidoxy, 4-nitrophenyl, azido, 2,4,6-triisopropylbenzenesulfonyl and diethoxyphosphoryloxy. "Halogen" means chlorine, bromine or iodine.

Unter den Verbindungen der Formel II ist 5′-Deoxy-5-­fluorcytidin bekannt [J. Med. Chem., 22, (1979) 1330]. Die anderen Verbindungen der Formel II können in an sich bekann­ter Weise [Chem. Pharm. Bull., 33, (1985) 2575] ausgehend von 5′-Deoxy-5-fluorcytidin oder von 5′-Deoxy-5-fluoruridin her­gestellt werden.5'-Deoxy-5-fluorocytidine is known from the compounds of the formula II [J. Med. Chem., 22 , (1979) 1330]. The other compounds of the formula II can be prepared in a manner known per se [Chem. Pharm. Bull., 33 , (1985) 2575] starting from 5'-deoxy-5-fluorocytidine or from 5'-deoxy-5-fluorouridine.

Die im obigen Verfahren verwendete Verbindungen der Formel XCOR⁴ sind Säurehalogenide, Säureanhydride, ge­mischte Anhydride (hergestellt durch Reaktion von R⁴COOH mit 2,4,6-Triisopropylbenzolsulfonylchlorid oder Diäthyl­chlorphosphat, worin R⁴ die obige Bedeutung hat) aktivierte Ester, wie N-Hydroxysuccinimidester, N-Hydroxyphthalimidester oder 4-Nitrophenylester; Acylazide oder gemischte Carbon­säureanhydride. Die Verbindungen der Formel YCOR¹⁰ sind Alkoxycarbonylhalogenide, Aralkoxycarbonylhalogenide, Alkyl­thiocarbonylhalogenide oder Aralkylthiocarbonylhalogenide.The compounds of the formula XCOR⁴ used in the above process are acid halides, acid anhydrides, mixed anhydrides (prepared by reaction of R⁴COOH with 2,4,6-triisopropylbenzenesulfonyl chloride or diethyl chlorophosphate, in which R⁴ has the above meaning) activated esters, such as N-hydroxysuccinimide esters, N- Hydroxyphthalimide ester or 4-nitrophenyl ester; Acylazide or mixed carboxylic acid anhydrides. The compounds of formula YCOR¹⁰ are alkoxycarbonyl halides, aralkoxycarbonyl halides, alkyl thiocarbonyl halides or aralkyl thiocarbonyl halides.

Die Reaktion einer Verbindung der Formel II mit einer Verbindung der Formel XCOR⁴ oder YCOR¹⁰ kann man in einem Lösungsmittel, wie Pyridin, Dioxan, Tetrahydrofuran, Aceto­nitril, Chloroform, Dichlormethan, Methanol, Aethanol oder Wasser oder Gemische davon durchführen, in Gegenwart eines Säureakzeptors, wie Triäthylamin, Pyridin, Picolin, Dimethyl­aminopyridin, Lutidin, N,N-Dimethylanilin oder eines Alkali­metallhydroxids, -carbonats oder -phosphats. Die Reaktion kann in einem breiten Temperaturbereich durchgeführt werden, zweckmässig jedoch zwischen etwa 0 und 120°C, vorzugsweise zwischen 0 und 50°C. Für 1 Mol einer Verbindung der Formel II werden 1, 2 oder 3 Mol oder ein Ueberschuss einer Verbindung der Formel XCOR⁴ oder YCOR¹⁰ verwendet.The reaction of a compound of formula II with a compound of formula XCOR⁴ or YCOR¹⁰ can be carried out in a solvent such as pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, dichloromethane, methanol, ethanol or water or mixtures thereof, in the presence of an acid acceptor, such as Triethylamine, pyridine, picoline, dimethylaminopyridine, lutidine, N, N-dimethylaniline or an alkali metal hydroxide, carbonate or phosphate. The reaction can be carried out over a wide temperature range However, expediently between about 0 and 120 ° C, preferably between 0 and 50 ° C. For 1 mole of a compound of formula II 1, 2 or 3 moles or an excess of a compound of formula XCOR⁴ or YCOR¹⁰ are used.

Die Abspaltung einer Schutzgruppe kann in an sich bekann­ter Weise durchgeführt werden.A protective group can be split off in a manner known per se.

Die Verbindungen der vorliegenden Erfindung können in an sich bekannter Weise isoliert und gereinigt werden, z.B. durch Abdampfen, Filtrierung, Extraktion, Abfällen, Chromato­graphie und/oder Umkristallisation.The compounds of the present invention can be isolated and purified in a manner known per se, e.g. by evaporation, filtration, extraction, waste, chromatography and / or recrystallization.

Die Verbindungen der Formel I können als Solvate, insbe­sondere als Hydrate vorliegen. Die Hydrierung kann im Laufe der Herstellung oder als Resultat der hygroskopischen Eigen­schaften eines ursprünglich wasserfreien Produktes erfolgen. Zur Herstellung eines Hydrats kann ein vollständig oder teil­weise wasserfreies Produkt, z.B. bei etwa 10 bis 40°C einer feuchten Atmosphäre ausgesetzt werden. Solvate mit pharmazeu­tisch anwendbaren Lösungsmitteln, wie Aethanol, können z.B. während einer Kristallisation entstehen.The compounds of formula I can exist as solvates, in particular as hydrates. The hydrogenation can take place during production or as a result of the hygroscopic properties of an originally anhydrous product. A completely or partially anhydrous product, e.g. exposed to a humid atmosphere at around 10 to 40 ° C. Solvates with pharmaceutically acceptable solvents such as ethanol can e.g. arise during crystallization.

Die Verbindungen der Formel I sowie die Hydrate und Solvate davon sind gegen Sarcoma 180, Meth A Fibrosarcoma und Lewis Lungenkarzinom bei Mäusen über einen breiten Dosie­rungsbereich sowohl oral wie parenteral wirksam und können als Antitumormittel Verwendung finden. 5-Fluoruracil und seine Derivate haben den Nachteil der intestinalen und immunosuppressiven Toxizität, was ihre Verwendung drastisch limitiert. Bei oraler Verabreichung sind die vorliegenden Verbindungen der Formel I viel weniger toxisch im intestina­len Trakt und für das Immunsystem als 5-Fluoruracil (J.A.C.S. 79, 1957, 4559) und die Vorläufer davon, wie Tegafur: Uracil, 1:4 (UFT) und 5′-Deoxy-5-fluoruridin (US 4071680). Daher können die Verbindungen der Formel I bei der Behandlung von verschiedenen Tumoren beim Menschen Verwendung finden.The compounds of the formula I and the hydrates and solvates thereof are both orally and parenterally active against Sarcoma 180, Meth A fibrosarcoma and Lewis lung carcinoma in mice over a wide dosage range and can be used as antitumor agents. 5-Fluorouracil and its derivatives have the disadvantage of intestinal and immunosuppressive toxicity, which drastically limits their use. When administered orally, the present compounds of formula I are much less toxic in the intestinal tract and to the immune system than 5-fluorouracil (JACS 79, 1957, 4559) and the precursors thereof, such as tegafur: uracil, 1: 4 (UFT) and 5 'Deoxy-5-fluorouridine (US 4071680). The compounds of formula I can therefore be used in the treatment of various tumors in humans.

Die Erfindung betrifft ebenfalls pharmazeutische Präparate, die eine oder mehrere Verbindungen der Formel I enthalten, sowie die Verwendung dieser Verbindungen zur Herstellung von Arzneimitteln zur Behandlung von Tumoren.The invention also relates to pharmaceutical preparations which contain one or more compounds of the formula I and the use of these compounds for the production of medicaments for the treatment of tumors.

Die Verbindungen der Formel I kann man dem Menschen oral oder nicht oral verabreichen, gegebenenfalls unter Zusatz eines verträglichen Trägermaterials. Letzteres kann eine für die enterale, perkutane oder parenterale Verabreichung geeignete organische oder anorganische inerte Substanz sein, wie Wasser, Gelatine, Gummi arabicum, Lactose, Stärke, Magnesiumstearat, Talk, pflanzliche Oele oder Polyalkylen­glykole. Die pharmazeutischen Präparate können in fester Form als Tabletten, Dragées, Granulate, Kapseln, Suppositorien oder als enteral verabreichbare Tabletten, Granulate oder Kapseln; in halbfester Form als Salben oder in flüssiger Form als Lösungen, Suspensionen oder Emulsionen vorliegen. Sie können sterilisiert sein und/oder weitere Hilfsmittel, wie Konservierungs- oder Stabilisierungsmittel, Emulgatoren, Riechstoffe, Salze zur Veränderung des osmotischen Druckes oder Puffer enthalten. Sie können in an sich bekannter Weise hergestellt werden.The compounds of formula I can be administered orally or non-orally to humans, optionally with the addition of a compatible carrier material. The latter can be an organic or inorganic inert substance suitable for enteral, percutaneous or parenteral administration, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils or polyalkylene glycols. The pharmaceutical preparations can be in solid form as tablets, dragees, granules, capsules, suppositories or as enterally administrable tablets, granules or capsules; are in semi-solid form as ointments or in liquid form as solutions, suspensions or emulsions. They can be sterilized and / or contain other auxiliaries, such as preservatives or stabilizers, emulsifiers, fragrances, salts for changing the osmotic pressure or buffers. They can be produced in a manner known per se.

Die Verbindungen der Formel I können einzeln oder als Gemische von zwei oder mehr Verwendung finden, wobei der Gehalt an Wirkstoff im Bereich von etwa 0,1 bis 99,5%, vorzugsweise 0,5 bis 95% des Gesamtgewichts des Präparats, liegt. Die Präparate können auch weitere pharmazeutisch wirksame Substanzen enthalten.The compounds of the formula I can be used individually or as mixtures of two or more, the active ingredient content being in the range from about 0.1 to 99.5%, preferably 0.5 to 95%, of the total weight of the preparation. The preparations can also contain other pharmaceutically active substances.

Die tägliche Dosis der Verbindungen der Formel I hängt von dem Gewicht des Patienten und der zu behandelnden Krank­heit ab, liegt jedoch im allgemeinen im Bereich von 0,5 bis 700, vorzugsweise von etwa 3 bis 500 mg/kg Körpergewicht. Die Antitumorwirksamkeit der Verbindungen der Formel I wird in den folgenden Versuchen veranschaulicht:The daily dose of the compounds of formula I depends on the weight of the patient and the disease to be treated, but is generally in the range from 0.5 to 700, preferably from about 3 to 500 mg / kg body weight. The antitumor activity of the compounds of the formula I is illustrated in the following experiments:

Antitumorwirkung gegen Sarcoma 180Antitumor activity against Sarcoma 180

Sarcoma 180 Zellen (2 x 10⁶ Zellen) werden am Tag 0 Mäusen (20-22 g) subkutan implantiert. Die Testsubstanzen werden täglich vom Tag 1 bis zum Tag 7 oral verabreicht. Die Tiere werden am Tag 14 getötet und die Tumoren werden heraus­genommen und gewogen. Die in der nachfolgenden angegebene Hemmung des Tumorwachstums in Tabelle 1 wird wie folgt ermittelt:

% Hemmung = (1 - T/C) x 100

T = Gewicht der Tumoren der behandelten Gruppe
C = Gewicht der Tumoren der Kontrollgruppe.

Figure imgb0003
Sarcoma 180 cells (2 x 10⁶ cells) are implanted subcutaneously in day 0 mice (20-22 g). The test substances are administered orally daily from day 1 to day 7. The animals are sacrificed on day 14 and the tumors are removed and weighed. The inhibition of tumor growth shown in Table 1 below is determined as follows:

% Inhibition = (1 - T / C) x 100

T = weight of the tumors of the treated group
C = weight of the tumors of the control group.
Figure imgb0003

Antitumorwirksamkeit gegen Meth A FibrosarcomaAntitumor activity against Meth A fibrosarcoma

Meth A Fibrosarcoma Zellen (2 x 10⁵ Zellen) werden Mäusen (21-22 g) subkutan implantiert. Der Versuch gegen Meth A Fibrosarcoma und die Ermittlung der Hemmung des Tumor­wachstums wurde in ähnlicher Weise wie beim Versuch gegen Sarcoma 180 durchgeführt. Die Resultate sind in der Tabelle 2 angegeben.Meth A Fibrosarcoma cells (2 x 10⁵ cells) are implanted subcutaneously in mice (21-22 g). The test against Meth A fibrosarcoma and the determination of the inhibition of tumor growth was carried out in a similar manner to the test against Sarcoma 180. The results are shown in Table 2.

In ähnlicher Weise wurde die Antitumorwirksamkeit der Verbindung des vorliegenden Beispiels 3 mit derjenigen von 5′-Deoxy-5-fluoruridin verglichen. Die Resultate sind in der Tabelle 3 angegeben. Am Tag 8 des Versuchs wurde der Kot beobachtet. Die Resultate zeigen, dass die Verbindung des Beispiels 3 höhere eine Antitumorwirksamkeit und eine niedrigere Toxizität als 5′-Deoxy-5-fluoruridin aufweist. Im gleichen Experiment verursachte die Verbindung des Beispiels 3 keine Diarrhea während letztere der die Dosis limitierende Faktor von 5′-Deoxy-5-fluoruridin darstellt.

Figure imgb0004
Figure imgb0005
Figure imgb0006
 Similarly, the antitumor activity of the compound of Example 3 was compared to that of 5'-deoxy-5-fluorouridine. The results are shown in Table 3. The faeces were observed on day 8 of the experiment. The results show that the compound of Example 3 has higher anti-tumor activity and lower toxicity than 5'-deoxy-5-fluorouridine. In the same experiment, the compound of Example 3 did not cause diarrhea, the latter being the dose limiting factor of 5'-deoxy-5-fluorouridine.
Figure imgb0004
Figure imgb0005
Figure imgb0006

Antitumorwirksamkeit gegen Lewis-LungenkarzinomAntitumor activity against Lewis lung carcinoma

Die Antitumorwirksamkeit der Verbindung des vorliegenden Beispiels 1 wurde mit derjenigen von 5′-Deoxy-5-fluoruridin und des Kombinationspräparats, UFT (Tegafur: Uracil, 1:4) verglichen. Mäusen wurde am Tag 0 Lewis-Lungenkarzinom (10⁶ Zellen) subkutan inokuliert. Die Verbindungen wurden täglich 14 mal ab Tag 1 oral verabreicht. Die effektive Dosis (ED₅₀), bei der das Wachstum des Tumors um 50% gehemmt wurde und die toxischen Dosen wurden ermittelt. Der thera­peutische Index (toxische Dose/ED₅₀) sind in der Tabelle 4 angegeben. Die Resultate zeigen, dass die Verbindung des Beispiels 1 einen höheren therapeutischen Index hat als die klassischen Vorläufer von 5-Fluoruracil, 5′-Deoxy-5-fluor­uridin und UFT. Sie ist weniger toxisch im intestinalen Trakt (Diarrhea) und in den für die Immunität verantwortlichen Organe (Thymus und Knochenmark) und weist daher einen höheren Sicherheitsgrad auf. Tabelle 4 Verbindung (Beispiel Nr.) Therapeutischer Index (Toxische Dose/ED₅₀ *) Max. Dosis ohne Diarrhea (A)** 10% Körpergewicht Abnahme (B)** 50% Thymus-Einschrumpfung (C)** 50% Reduktion der Anzahl Zellen im Knochenmark (D)** 1 >13 >13 11.3 10.7 5′-Deoxy-5-fluoruridin 5 6.4 5 - 10 5 - 10 UFT 1.5 2.5 1.1 1.5 - 2.9 * Die ED₅₀-Werte der Verbindung des Beispiels 1 von 5′-Deoxy-5-fluoruridin und von UFT am Tag 15 sind 0,15, 0,20 bzw. 0,086 mMol/kg/Tag. ** Die Toxizitäten wurden am Tag 10(A), 7(B), 14(C) und 14(D) ermittelt. The antitumor activity of the compound of the present example 1 was compared with that of 5'-deoxy-5-fluorouridine and the combination preparation, UFT (Tegafur: uracil, 1: 4). Mice were subcutaneously inoculated with Lewis lung carcinoma (10 0 cells) on day 0. The compounds were administered orally 14 times a day from day 1. The effective dose (ED₅₀) at which tumor growth was inhibited by 50% and the toxic doses were determined. The therapeutic index (toxic dose / ED₅₀) are given in Table 4. The results show that the compound of Example 1 has a higher therapeutic index than the classic precursors of 5-fluorouracil, 5'-deoxy-5-fluorouridine and UFT. It is less toxic in the intestinal tract (diarrhea) and in those responsible for immunity Organs (thymus and bone marrow) and therefore has a higher level of security. Table 4 Connection (example number) Therapeutic index (toxic dose / ED₅₀ *) Max. Dose without diarrhea (A) ** 10% body weight loss (B) ** 50% thymus shrinkage (C) ** 50% reduction in the number of cells in the bone marrow (D) ** 1 > 13 > 13 11.3 10.7 5'-deoxy-5-fluorouridine 5 6.4 5 - 10 5 - 10 UFT 1.5 2.5 1.1 1.5 - 2.9 * The ED₅₀ values of the compound of Example 1 of 5'-deoxy-5-fluorouridine and of UFT on day 15 are 0.15, 0.20 and 0.086 mmol / kg / day. ** The toxicities were determined on days 10 (A), 7 (B), 14 (C) and 14 (D).

Antitumorwirksamkeit gegen Sarcoma 180, Meta A Fibrosarcoma und UV 2237 FibrosarcomaAntitumor activity against Sarcoma 180, Meta A Fibrosarcoma and UV 2237 Fibrosarcoma

Die Antitumorwirksamkeit der Verbindung des vorliegenden Beispiels 1 wurde in drei Murintumormodellen mit derjenigen von 5′-Deoxy-5-fluoruridin und 5′-Deoxy-5-fluorcytidin verglichen. Mäuse wurden am Tag 0 subkutan mit Sarcoma 180, Meth A Fibrosarcoma und UV 2237 Fibrosarcoma inokuliert. Ab Tag 1 wurden die Versuchssubstanzen 7 mal den Mäusen oral verabreicht. Die Wirksamkeit wurde als therapeutischer Index (EDmax/ED₅₀) am Tag 14 nach Tumorinokulation gemessen. EDmax ist die Dosis, bei der die Hemmung des Tumorwachstums maximal ist. Die Resultate sind in der Tabelle 5 angegeben. Tabelle 5 Wirksamkeit gegen Sarcom 180, Meth A Fibrosarcoma und UV 2237 Fibrosarcoma Verbindung (Beisp.-Nr.) Therapeutischer Index S 180 Meth A UV 2237 1 2.3 2.0 4.8 5′-Deoxy-5-fluorcytidin 2.0 1.2 1.0 5′-Deoxy-5-fluoruridin 2.4 1.1 1.6 The antitumor activity of the compound of Example 1 was compared in three murine tumor models with that of 5'-deoxy-5-fluorouridine and 5'-deoxy-5-fluorocytidine. Mice were inoculated subcutaneously on day 0 with Sarcoma 180, Meth A Fibrosarcoma and UV 2237 Fibrosarcoma. From day 1, the test substances were administered orally to the mice 7 times. Efficacy was measured as a therapeutic index (ED max / ED₅₀) on day 14 after tumor inoculation. ED max is the dose at which tumor growth is maximally inhibited. The results are shown in Table 5. Table 5 Efficacy against Sarcom 180, Meth A Fibrosarcoma and UV 2237 Fibrosarcoma Connection (example no.) Therapeutic index S 180 Meth A UV 2237 1 2.3 2.0 4.8 5'-deoxy-5-fluorocytidine 2.0 1.2 1.0 5'-deoxy-5-fluorouridine 2.4 1.1 1.6

Akute Toxizitätacute toxicity

Die akute Toxizität (LD₅₀) der Verbindungen der vor­liegenden Beispiele 1, 5, 9, 24, 34, 46 und 47 beträgt mehr als 2000 mg/kg bei oraler Verabreichung an Mäusen.The acute toxicity (LD₅₀) of the compounds of the present examples 1, 5, 9, 24, 34, 46 and 47 is more than 2000 mg / kg when administered orally to mice.

Die folgenden Beispiele veranschaulichen die Erfindung.The following examples illustrate the invention.

ReferenzbeispielReference example

a) 245 mg 5′-Deoxy-5-fluorcytidin, 354 mg t-Butyldimethyl­silylchlorid und 284 mg Imidazol werden in 1,5 ml Dimethyl­formamid gelöst und 18 Stunden unter Stickstoff gerührt. Das Gemisch wird dann in Wasser geschüttet und mit Aethylacetat extrahiert. Der Extrakt wird mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck einge­engt. Man erhält 431 mg 2′, 3′-Bis-O-(t-butyldimethylsilyl)-­5′-deoxy-5-fluorcytidin, MS 473 (M⁺).a) 245 mg of 5'-deoxy-5-fluorocytidine, 354 mg of t-butyldimethylsilyl chloride and 284 mg of imidazole are dissolved in 1.5 ml of dimethylformamide and stirred under nitrogen for 18 hours. The mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated under reduced pressure. 431 mg of 2 ′, 3′-bis-O- (t-butyldimethylsilyl) -5′-deoxy-5-fluorocytidine, MS 473 (M⁺) are obtained.

b) Eine Lösung von 490 mg 5′-Deoxy-5-fluorcytidin, 418 mg p-Toluolsulfonsäure-monohydrat und 984 µl 2,2-Dimethoxy­propan in 10 ml Aceton wird 1,5 Stunden gerührt. Der Lösung werden 900 mg Natriumbicarbonat zugesetzt und das Gemisch wird 4 Stunden gerührt. Der Niederschlag wird abfiltriert und mit Aceton gewaschen. Die Filtrate werden unter vermindertem Druck eingeengt. Der Rückstand wird über Silicagel mit Dichlormethan-Methanol gereinigt. Man erhält 570 mg 5′-Deoxy-­5-fluor-2′,3′-O-isopropylidencytidin, MS 286 (MH⁺), Smp. des Picrats 169-171°C.b) A solution of 490 mg of 5'-deoxy-5-fluorocytidine, 418 mg of p-toluenesulfonic acid monohydrate and 984 μl of 2,2-dimethoxypropane in 10 ml of acetone is stirred for 1.5 hours. 900 mg of sodium bicarbonate are added to the solution and the mixture is stirred for 4 hours. The precipitate is filtered off and washed with acetone. The filtrates are concentrated under reduced pressure. The residue is purified over silica gel with dichloromethane-methanol. 570 mg of 5'-deoxy-5-fluoro-2 ', 3'-O-isopropylidencytidine, MS 286 (MH⁺), mp. Des Picrats 169-171 ° C.

Beispiel 1example 1

1(a) 9,46 g 2′,3′-Bis-O-(t-butyldimethylsilyl)-5′-deoxy-­5-fluorcytidin, hergestellt nach Referenzbeispiel a), 3,48 g n-Buttersäureanhydrid und 2,93 g 4-Dimethylaminopyridin werden in 150 ml Methylenchlorid gelöst und über Nacht gerührt, dann mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Man erhält 9,75 g N⁴-Butyryl-2′,3′-bis-O-(t-butyldimethylsilyl)-­5′-deoxy-5-fluorcytidin¸ MS 544 (MH⁺).1 (a) 9.46 g of 2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluorocytidine, prepared according to reference example a), 3.48 g of n-butyric anhydride and 2.93 g of 4-dimethylaminopyridine are dissolved in 150 ml of methylene chloride and stirred overnight, then washed with water, dried over sodium sulfate and concentrated under reduced pressure. 9.75 g of N⁴-butyryl-2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluorocytidine¸ MS 544 (MH⁺) are obtained.

1(b) 9,75 g des Produkts von Beispiel 1(a) werden in 80 ml Tetrahydrofuran enthaltend 80 mMol Tetrabutylammoniumfluorid gelöst und 1,5 Stunden gerührt. Nach Entfernung des Lösungs­mittels unter vermindertem Druck wird der Rückstand über Silicagel mit Aethylacetat-Methanol gefolgt durch Umkristal­lisation aus Methanol gereinigt. Man erhält 4,5 g N⁴-Butyryl-5′-deoxy-5-fluorcytidin, Smp. 156-157°C; MS 316 (MH⁺).1 (b) 9.75 g of the product from Example 1 (a) are dissolved in 80 ml of tetrahydrofuran containing 80 mmol of tetrabutylammonium fluoride and stirred for 1.5 hours. After removal of the solvent under reduced pressure, the residue is over Purified silica gel with ethyl acetate-methanol followed by recrystallization from methanol. 4.5 g of N⁴-butyryl-5'-deoxy-5-fluorocytidine, mp. 156-157 ° C; MS 316 (MH⁺).

Die folgenden Verbindungen wurden in ähnlicher Weise wie in Beispiel 1 erhalten:

Figure imgb0007
The following compounds were obtained in a similar manner to that in Example 1:
Figure imgb0007

Beispiel 4Example 4

4(a) Einer Lösung von 14,19 g 2′,3′-Bis-O-(t-butyldimethyl­silyl)-5′-deoxy-5-fluorcytidin in 150 ml trockenem Pyridin werden 3,84 g n-Butyrylchlorid unter Rühren zugetropft. Das Gemisch wird über Nacht gerührt. Pyridin wird unter ver­mindertem Druck entfernt und der Rückstand wird zwischen Wasser und Aethylacetat verteilt. Die Aethylacetatschicht wird mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Der Rückstand wird über Silicagel mit n-Hexan-Aethylacetat gereinigt. Man erhält 15,32 g N⁴-Butyryl-2′,3′-bis-O-(t-butyldimethylsilyl)-5′-­ deoxy-5-fluorcytidin.4 (a) A solution of 14.19 g of 2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluorocytidine in 150 ml of dry pyridine, 3.84 g of n-butyryl chloride are stirred dripped. The mixture is stirred overnight. Pyridine is removed under reduced pressure and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified on silica gel with n-hexane-ethyl acetate. 15.32 g of N⁴-butyryl-2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'- deoxy-5-fluorocytidine.

4(b) Das Produkt des Beispiels 4(a) wird in Analogie zu Beispiel 1(b) behandelt. Man erhält farblose Kristalle von N⁴-Butyryl-5′-deoxy-5-fluorcytidin.4 (b) The product of Example 4 (a) is treated in analogy to Example 1 (b). Colorless crystals of N⁴-butyryl-5'-deoxy-5-fluorocytidine are obtained.

Die folgenden Verbindungen werden analog Beispiel 4 hergestellt:

Figure imgb0008
Figure imgb0009
Figure imgb0010
Figure imgb0011
 The following compounds are prepared analogously to Example 4:
Figure imgb0008
Figure imgb0009
Figure imgb0010
Figure imgb0011

Beispiel 43Example 43

735 mg 5′-Deoxy-5-fluorcytidin und 1,04 g Buttersäure­anhydrid werden in 20 ml 75% wässrigem Dioxan gelöst und 18 Stunden gerührt. Nach Entfernung des Lösungsmittel wird der Rückstand durch Chromatographie über Silicagel gereinigt. Man erhält 420 mg N⁴-Butyryl-5′-deoxy-5-fluorcytidin, Smp. 156-157°C; MS 316 (MH⁺).735 mg of 5'-deoxy-5-fluorocytidine and 1.04 g of butyric anhydride are dissolved in 20 ml of 75% aqueous dioxane and stirred for 18 hours. After removal of the solvent, the residue is purified by chromatography on silica gel. 420 mg of N⁴-butyryl-5'-deoxy-5-fluorocytidine are obtained, mp. 156-157 ° C .; MS 316 (MH⁺).

Beispiel 44Example 44

(1) 4,9 g 5′-Deoxy-5-fluorcytidin und 5,58 ml Trimethylsilyl­chlorid werden in 50 ml trockenem Pyridin gelöst und 2 Stun­den gerührt. Dem Reaktionsgemisch werden 2,09 ml Aethylchlor­thioformat zugesetzt. Nach 2,5-stündigem Rühren wird das Pyridin unter vermindertem Druck abgedampft. Der Rückstand wird zwischen Wasser und Aethylacetat verteilt. Die organi­sche Schicht wird mit Wasser gewaschen¸ über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Dem Rück­stand werden 5 g Zitronensäure und 80 ml Methanol zugesetzt. Das Gemisch wird 1 Stunde gerührt. Nach Entfernen des Lösungsmittels unter vermindertem Druck wird der Rückstand über Silicagel mit Methanol-Dichlormethan gefolgt durch Umkristallisation aus Dichlormethan gereinigt. Man erhält 2,66 g 5′-Deoxy-N⁴-[(äthylthio)carbonyl]-5-fluorcytidin, Smp. 138-139°C (Zers.); MS 334 (MH⁺).(1) 4.9 g of 5'-deoxy-5-fluorocytidine and 5.58 ml of trimethylsilyl chloride are dissolved in 50 ml of dry pyridine and stirred for 2 hours. 2.09 ml of ethyl chlorothioformate are added to the reaction mixture. After stirring for 2.5 hours, the pyridine is evaporated under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic layer is washed with water¸ dried over sodium sulfate and concentrated under reduced pressure. 5 g of citric acid and 80 ml of methanol are added to the residue. The mixture is stirred for 1 hour. After removing the solvent under reduced pressure, the residue is purified on silica gel with methanol-dichloromethane followed by recrystallization from dichloromethane. 2.66 g of 5'-deoxy-N⁴ - [(ethylthio) carbonyl] -5-fluorocytidine, mp. 138-139 ° C. (dec.); MS 334 (MH⁺).

(2)(a) Einer Lösung von 1 g 5′-Deoxy-5-fluor-2′,3′-O-iso­propylidencytidin erhalten nach Referenzbeispiel b) in 8 ml Pyridin werden 365 µl Aethylchlorthioformat bei 0°C unter Rühren zugesetzt und das Gemisch wird über Nacht gerührt. Das Reaktionsgemisch wird unter vermindertem Druck eingeengt und der Rückstand wird zwischen Aethylacetat und Wasser verteilt. Die organische Schicht wird mit einer Natriumbicarbonatlösung und Wasser gewaschen und über Natriumsulfat getrocknet. Nach Entfernung des Lösungsmittels wird der Rückstand über Silica­gel mit CHCl₃ gereinigt. Man erhält 510 mg 5′-Deoxy-N⁴-­ [(äthylthio)carbonyl]-5-fluor-2′,3′-O-isopropylidencytidin, MS 374 (MH⁺).(2) (a) A solution of 1 g of 5'-deoxy-5-fluoro-2 ', 3'-O-isopropylidencytidine obtained according to reference example b) in 8 ml of pyridine, 365 µl of ethyl chlorothioformate are added at 0 ° C with stirring and the mixture is stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic layer is washed with a sodium bicarbonate solution and water and dried over sodium sulfate. After removal of the solvent, the residue is purified on silica gel with CHCl₃. 510 mg of 5'-deoxy-N⁴- [(ethylthio) carbonyl] -5-fluoro-2 ′, 3′-O-isopropylidencytidine, MS 374 (MH⁺).

(b) Einer Lösung von 150 mg des Produkts von Beispiel 44(2)(a) in 50% wässrigem Aethanol werden 150 mg Dowex 50 (H⁺) zugesetzt und das Gemisch wird 4 Stunden unter Rühren bei 50-60°C erhitzt. Das Dowex 50 wird abfiltriert und das Filtrat wird unter vermindertem Druck zur Trockene einge­dampft. Der Rückstand wird über Silicagel mit CHCl₃-Aceton und dann durch Umkristallisation aus Dichlormethan gereinigt. Man erhält 5′-Deoxy-N⁴-[(äthylthio)carbonyl]-5-fluor­cytidin, Smp. 138-139°C (Zers.); MS 334 (MH⁺).(b) 150 mg of Dowex 50 (H⁺) are added to a solution of 150 mg of the product from Example 44 (2) (a) in 50% aqueous ethanol and the mixture is heated at 50-60 ° C. with stirring for 4 hours. The Dowex 50 is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue is purified on silica gel with CHCl₃ acetone and then by recrystallization from dichloromethane. This gives 5'-deoxy-N⁴ - [(ethylthio) carbonyl] -5-fluorocytidine, mp. 138-139 ° C (dec.); MS 334 (MH⁺).

Die folgenden Verbindungen werden in Analogie zu Beispiel 44(1) erhalten:

Figure imgb0012
The following compounds are obtained analogously to Example 44 (1):
Figure imgb0012

Beispiel 48Example 48

Eine Lösung von 0,42 g Piperonylsäure in trockenem Aceto­nitril (5 ml) enthaltend 0,36 ml Triäthylamin wird mit 0,37 ml Diäthylchlorphosphat 1 Stunde gerührt. Dem Reaktions­gemisch werden 1,0 g 2′,3′-Bis-O-(t-butyldimethylsilyl)-5′-­deoxy-5-fluorcytidin, hergestellt nach Beispiel a), 0,36 ml Triäthylamin und 0,05 g 4-Dimethylaminopyridin zugesetzt. Nach 12-stündigem Rühren wird das Acetonitril unter ver­mindertem Druck abgedampft. Der Rückstand wird zwischen Wasser und Aether verteilt. Die organische Schicht wird mit Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Das erhaltene Pulver wird in 6,3 ml Tetrahydrofuran enthaltend 1,65 g Tetrabutylammonium­fluorid gelöst und das Reaktionsgemisch wird 1 Stunde gerührt. Nach Entfernung des Lösungsmittels unter verminder­tem Druck wird der Rückstand über Silicagel mit Isopropanol-­Dichlormethan und dann Umkristallisation aus Aethyl­acetat gereinigt. Man erhält 0,5 g 5′-Deoxy-5-fluor-N⁴-­piperonyloylcytidin, Smp. 124-125°C, MS 394 (MH⁺).A solution of 0.42 g of piperonylic acid in dry acetonitrile (5 ml) containing 0.36 ml of triethylamine is stirred with 0.37 ml of diethyl chlorophosphate for 1 hour. 1.0 g of 2 ′, 3′-bis-O- (t-butyldimethylsilyl) -5′-deoxy-5-fluorocytidine, prepared according to Example a), 0.36 ml of triethylamine and 0.05 g of 4- Dimethylaminopyridine added. After stirring for 12 hours, the acetonitrile is evaporated under reduced pressure. The residue is partitioned between water and ether. The organic layer is washed with water, dried over sodium sulfate and under concentrated under reduced pressure. The powder obtained is dissolved in 6.3 ml of tetrahydrofuran containing 1.65 g of tetrabutylammonium fluoride and the reaction mixture is stirred for 1 hour. After removal of the solvent under reduced pressure, the residue is purified on silica gel with isopropanol-dichloromethane and then recrystallization from ethyl acetate. 0.5 g of 5'-deoxy-5-fluoro-N⁴-piperonyloylcytidine, mp. 124-125 ° C, MS 394 (MH⁺).

Die folgende Verbindung wird in Analogie zu Beispiel 48 erhalten:

Figure imgb0013
The following compound is obtained in analogy to Example 48:
Figure imgb0013

Beispiel 50Example 50

0,355 g 3-Furancarbonsäure und 0,96 g 2,4,6-Triisopropyl­benzolsulfonsäurechlorid werden in 5 ml trockenem Pyridin gelöst. Das Gemisch wird 1 Stunde gerührt. Dem Gemisch werden 1 g 2′,3′-Bis-O-(t-butyldimethylsilyl)-5′-deoxy-5-fluor­cytidin, erhalten im Referenzbeispiel a), und 0,80 g 4-Dimethylaminopyridin zugesetzt. Nach 12 Stunden Rühren wird das Pyridin unter vermindertem Druck abgedampft. Nach Behand­lung des Rückstands wie im Beispiel 46 erhält man 0,55 g 5′-Deoxy-5-fluor-N⁴-(3-furoyl)cytidin, Smp. 173-174°C (Aethanol); MS 340 (MH⁺).0.355 g of 3-furan carboxylic acid and 0.96 g of 2,4,6-triisopropylbenzenesulfonic acid chloride are dissolved in 5 ml of dry pyridine. The mixture is stirred for 1 hour. 1 g of 2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluorocytidine, obtained in reference example a), and 0.80 g of 4-dimethylaminopyridine are added to the mixture. After stirring for 12 hours, the pyridine is evaporated off under reduced pressure. After treating the residue as in Example 46, 0.55 g of 5'-deoxy-5-fluoro-N⁴- (3-furoyl) cytidine, mp. 173-174 ° C (ethanol); MS 340 (MH⁺).

Die folgenden Verbindungen werden analog Beispiel 50 hergestellt:

Figure imgb0014
The following compounds are prepared analogously to Example 50:
Figure imgb0014

Beispiel 57Example 57

(a) Einer Lösung von 24,6 g 5′-Deoxy-5-fluoruridin in 150 ml trockenem Pyridin werden 24,5 ml Benzoylchlorid über 10 Minu­ten bei 0°C Rühren zugetropft und das Gemisch wird 5 Stunden bei Raumtemperatur gerührt. Nach Entfernen des Pyridins unter vermindertem Druck wird der Rückstand zwischen Wasser und Aethylacetat verteilt. Die organische Schicht wird mit gesättigter Natriumbicarbonatlösung und Wasser gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingeengt. Der Rückstand wird aus Aethylacetat-n-Hexan umkristallisiert und man erhält 38,9 g 2′,3′-Di-O-benzoyl-5′-­deoxy-5-fluoruridin, MS 455 (MH⁺).(a) To a solution of 24.6 g of 5'-deoxy-5-fluorouridine in 150 ml of dry pyridine, 24.5 ml of benzoyl chloride are added dropwise over 10 minutes at 0 ° C. and the mixture is stirred for 5 hours at room temperature. After removing the pyridine under reduced pressure, the residue is partitioned between water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate-n-hexane and 38.9 g of 2 ', 3'-di-O-benzoyl-5'-deoxy-5-fluorouridine, MS 455 (MH⁺) are obtained.

(b) Einem Gemisch von 0,8 ml N-Methylimidazol und 0,28 ml Phosphorylchlorid in 20 ml Acetonitril werden 500 mg 2′,3′-Di-O-benzoyl-5′-deoxy-5-fluoruridin bei 0°C zugesetzt. Nach 1,5-stündigem Rühren werden 2,5 ml 28% Ammoniumhydroxid bei 0°C zugesetzt und das Gemisch wird 1 Stunde bei Raum­temperatur gerührt. Das Acetonitril und das Ammoniak werden unter vermindertem Druck entfernt. Der Rückstand wird mit 1N HCl angesäuert und dann mit Aethylacetat extrahiert. Die organische Schicht wird mit Wasser gewaschen, über Natrium­sulfat getrocknet und unter vermindertem Druck eingeengt. Der Rückstand wird aus Aethylacetat umkristallisiert. Man erhält 155 mg 2′,3′-Di-O-benzoyl-5′-deoxy-5-fluorcytidin, Smp. 192-194°C; MS 476 (M+Na)⁺.(b) A mixture of 0.8 ml of N-methylimidazole and 0.28 ml of phosphoryl chloride in 20 ml of acetonitrile is 500 mg of 2 ', 3'-di-O-benzoyl-5'-deoxy-5-fluorouridine at 0 ° C added. After stirring for 1.5 hours, 2.5 ml of 28% ammonium hydroxide are added at 0 ° C. and the mixture is stirred at room temperature for 1 hour. The acetonitrile and ammonia are removed under reduced pressure. The residue is acidified with 1N HCl and then extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate. 155 mg of 2 ', 3'-di-O-benzoyl-5'-deoxy-5-fluorocytidine are obtained, mp. 192-194 ° C; MS 476 (M + Na) ⁺.

Beispiel 58Example 58

(a) 0,57 ml eisgekühltem Essigsäureanhydrid werden 286 µl 99% Ameisensäure zugetropft. Die Lösung wird 15 Minuten bei 0°C und 50 Minuten bei 50°C gerührt und dann auf 0°C abge­kühlt. Der Lösung werden 473 mg 2′,3′-Bis-O-(t-butyldimethyl­silyl)-5′-deoxy-5-fluorcytidin hergestellt nach Referenz­beispiel a) in 5 ml trockenem Pyridin bei 0°C zugefügt. Das Reaktionsgemisch wird 10 Minuten bei 0°C und 26 Stunden bei Raumtemperatur gerührt. Nach Entfernen des Lösungsmittels unter vermindertem Druck wird der Rückstand zwischen Wasser und Aethylacetat aufgeteilt. Die organische Schicht wird mit gesättiger Natriumbicarbonatlösung und Wasser gewaschen und über Natriumsulfat getrocknet. Das Aethylacetat wird unter vermindertem Druck abgedampft und der Rückstand wird über Silicagel mit n-Hexan-Aethylacetat und dann durch Umkristal­lisation aus n-Hexan-Aethylacetat gereinigt. Man erhält 144 mg 2′,3′-Bis-O-(t-butyldimethylsilyl)-5′-deoxy-5-fluor -N⁴-formylcytidin¸ Smp. 188°C (Zers.); MS 502 (MH⁺).(a) 0.57 ml of ice-cooled acetic anhydride are added dropwise to 286 ul 99% formic acid. The solution is stirred for 15 minutes at 0 ° C and 50 minutes at 50 ° C and then cooled to 0 ° C. 473 mg of 2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluorocytidine prepared according to reference example a) in 5 ml of dry pyridine at 0 ° C. are added to the solution. The reaction mixture is 10 minutes at 0 ° C and 26 hours Room temperature stirred. After removing the solvent under reduced pressure, the residue is partitioned between water and ethyl acetate. The organic layer is washed with saturated sodium bicarbonate solution and water and dried over sodium sulfate. The ethyl acetate is evaporated under reduced pressure and the residue is purified on silica gel with n-hexane-ethyl acetate and then by recrystallization from n-hexane-ethyl acetate. 144 mg of 2 ', 3'-bis-O- (t-butyldimethylsilyl) -5'-deoxy-5-fluoro -N⁴-formylcytidine¸ mp. 188 ° C (dec.); MS 502 (MH⁺).

(b) Das Produkt des Beispiels 58(a) wird behandelt in Analogie zu Beispiel 1(b). Man erhält amorphes 5′-Deoxy-5-­fluor-N⁴-formylctidin¸ MS 274 (MH⁺).(b) The product of Example 58 (a) is treated in analogy to Example 1 (b). Amorphous 5'-deoxy-5-fluoro-N⁴-formylctidin¸ MS 274 (MH⁺) is obtained.

Beispiel 59Example 59

Einer Lösung von 245 mg 5′-Deoxy-5-fluorcytidin in 5 ml trockenem Pyridin werden unter Rühren bei 0°C 130 µl Benzoylchlorid zugesetzt. Das Gemisch wird 1 Stunde bei 0°C gerührt. Nach Entfernen des Lösungsmittels unter vermindertem Druck wird der Rückstand über Silicagel mit Dichlormethan-­Methanol und dann durch Umkristallisation aus Aethylacetat gereinigt. Man erhält 51 mg 3′-O-Benzoyl-5′-deoxy-5-fluor­cytidin, Smp. 127-129°C; MS 350 (MH⁺).130 µl of benzoyl chloride are added to a solution of 245 mg of 5'-deoxy-5-fluorocytidine in 5 ml of dry pyridine with stirring at 0 ° C. The mixture is stirred at 0 ° C for 1 hour. After removing the solvent under reduced pressure, the residue is purified on silica gel with dichloromethane-methanol and then by recrystallization from ethyl acetate. 51 mg of 3'-O-benzoyl-5'-deoxy-5-fluorocytidine are obtained, mp. 127-129 ° C; MS 350 (MH⁺).

Beispiel 60Example 60

Einer Lösung von 35 mg des Produkts von Beispiel 59 in 0,5 ml trockenem Pyridin werden 13,8 µl Trimethylsilyl­chlorid und nach 2-stündigem Rühren 12,6 µl Benzoylchlorid zugesetzt. Das Gemisch wird 1 Stunde gerührt. Nach Entfernen des Lösungsmittels unter vermindertem Druck wird der Rück­stand in 0,5 ml Methanol gelöst. Der Lösung werden 15 mg Kaliumcarbonat zugesetzt und das Reaktionsgemisch wird 30 Minuten bei 0°C gerührt. Nach Entfernen des Lösungsmittels unter vermindertem Druck wird der Rückstand zwischen Wasser und Aethylacetat aufgeteilt. Die organische Schicht wird über Magnesiumsulfat getrocknet und unter vermindertem Druck eingeengt. Der Rückstand wird über Silicagel mit Dichlor­methan-Methanol gereinigt. Man erhält 15 mg amorphes N⁴,3′-O-Dibenzoyl-5′-deoxy-5-fluorcytidin, MS 454 (MH⁺).13.8 μl of trimethylsilyl chloride are added to a solution of 35 mg of the product of Example 59 in 0.5 ml of dry pyridine and, after stirring for 2 hours, 12.6 μl of benzoyl chloride. The mixture is stirred for 1 hour. After removing the solvent under reduced pressure, the residue is dissolved in 0.5 ml of methanol. 15 mg of potassium carbonate are added to the solution and the reaction mixture is stirred at 0 ° C. for 30 minutes. After removing the solvent under reduced pressure, the residue is between water and ethyl acetate divided. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified over silica gel with dichloromethane-methanol. 15 mg of amorphous N⁴, 3'-O-dibenzoyl-5'-deoxy-5-fluorocytidine, MS 454 (MH⁺) are obtained.

Beispiel 61Example 61

245 mg 5′-Deoxy-5-fluorcytidin, 400 µl Benzoylchlorid und 122 mg 4-Dimethylaminopyridin werden in 5 ml trockenem Pyridin gelöst. Nach 3-stündigem Rühren wird das Pyridin unter vermindertem Druck entfernt. Der Rückstand wird zwischen Aethylacetat und Wasser verteilt. Die Aethylacetat­schicht wird über Magnesiumsulfat getrocknet und unter vermindertem Druck eingeengt. Der Rückstand wird aus Methanol umkristallisiert. Man erhält 280 mg N⁴,2′-0,3′-O-Tri­benzoyl-5′-deoxy-5-fluorcytidin, Smp. 158-160°C; MS 558 (MH⁺).245 mg of 5'-deoxy-5-fluorocytidine, 400 ul of benzoyl chloride and 122 mg of 4-dimethylaminopyridine are dissolved in 5 ml of dry pyridine. After stirring for 3 hours, the pyridine is removed under reduced pressure. The residue is partitioned between ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from methanol. This gives 280 mg of N 2, 2'-0.3'-O-tribenzoyl-5'-deoxy-5-fluorocytidine, mp. 158-160 ° C; MS 558 (MH⁺).

Die nachfolgenden Beispiele veranschaulichen pharmazeu­tische Präparate auf der Basis einer Verbindung nach der vorliegenden Erfindung.The following examples illustrate pharmaceutical preparations based on a compound according to the present invention.

Beispiel AExample A

Es werden in an sich bekannter Weise Gelatinesteckkapseln folgender Zusammensetzung hergestellt: N⁴-Butyryl-5′-deoxy-5-fluorcytidin 100 mg Maisstärke 20 mg Titaniumdioxid 385 mg Magnesiumstearat 5 mg Film 20 mg PEG 6000 3 mg Talk 10 mg Gesamtgewicht 543 mg Gelatin capsules of the following composition are produced in a manner known per se: N⁴-butyryl-5'-deoxy-5-fluorocytidine 100 mg Cornstarch 20 mg Titanium dioxide 385 mg Magnesium stearate 5 mg Movie 20 mg PEG 6000 3 mg Talk 10 mg total weight 543 mg

Beispiel BExample B

Es werden in an sich bekannter Weise Tabletten folgender Zusammensetzung hergestellt: N⁴-Butyryl-5′-deoxy-5-fluorcytidin 100 mg Lactose 25 mg Maisstärke 20,2 mg Hydroxypropylmethylcellulose 4 mg Magnesiumstearat 0,8 mg Film 10 mg PEG 6000 1,5 mg Talk 4,5 mg Gesamtgewicht 166 mg Tablets of the following composition are produced in a manner known per se: N⁴-butyryl-5'-deoxy-5-fluorocytidine 100 mg Lactose 25 mg Cornstarch 20.2 mg Hydroxypropylmethyl cellulose 4 mg Magnesium stearate 0.8 mg Movie 10 mg PEG 6000 1.5 mg Talk 4.5 mg total weight 166 mg

Beispiel CExample C

(1) 5 g N⁴-Butyryl-5′-deoxy-5-fluorcytidin werden in 75 ml destilliertem Wasser gelöst. Die Lösung wird einer bakterio­logischen Filtration unterworfen und dann aseptisch in 10 sterilen Fläschchen geschüttet. Die Lösung wird dann trocken gefroren, sodass jedes Fläschchen 500 mg sterilen trockenen Feststoff enthält.(1) 5 g of N⁴-butyryl-5'-deoxy-5-fluorocytidine are dissolved in 75 ml of distilled water. The solution is subjected to bacteriological filtration and then aseptically poured into 10 sterile vials. The solution is then frozen dry so that each vial contains 500 mg of sterile dry solid.

(2) Reines N⁴-Butyryl-5′-deoxy-5-fluorcytidin in einer Menge von mg pro Fläschchen oder Ampulle wird versiegelt und heiss sterilisiert.(2) Pure N⁴-butyryl-5'-deoxy-5-fluorocytidine in an amount of mg per vial or ampoule is sealed and hot sterilized.

Vor der Verwendung werden den obigen trockenen Dosie­rungsformen ein steriles wässriges Lösungsmittel, wie Wasser für Injektion oder isotonische Natriumchloridlösung oder 5% Dextrose¸ für parenterale Verabreichung zugesetzt.Before use, a sterile aqueous solvent such as water for injection or isotonic sodium chloride solution or 5% dextrose¸ for parenteral administration is added to the above dry dosage forms.

Claims (8)

1. 5′-Deoxy-5-fluorcytidinderivate der allgemeinen Formel
Figure imgb0015
 worin R¹, R² und R³ unabhängig voneinander Wasser­stoff oder eine unter physiologischen Bedingungen leicht abspaltbare Gruppe sind, mit der Bedingung, dass zumindest eines von R¹, R² und R³ eine unter physiologischen Bedingungen leicht abspaltbare Gruppe ist, sowie Hydrate oder Solvate der Verbindungen der Formel I.1. 5'-deoxy-5-fluorocytidine derivatives of the general formula
Figure imgb0015
 wherein R¹, R² and R³ are independently hydrogen or a group which is easily removable under physiological conditions, with the condition that at least one of R¹, R² and R³ is a group which is easily removable under physiological conditions, and hydrates or solvates of the compounds of the formula I. . 2. Verbindungen nach Anspruch 1, worin die leicht hydrolysierbaren Gruppen R¹, R² und R³ in der Formel I eine der Formel

R⁴CO-, R⁵OCO- oder R⁶SCO-

worin R⁴ Wasserstoff, Alkyl, Cycloalkyl, Oxoalkyl, Alkenyl, Aralkyl oder Aryl und R⁵ und R⁶ Alkyl oder Aralkyl sind.2. Compounds according to claim 1, wherein the easily hydrolyzable groups R¹, R² and R³ in the formula I one of the formula

R⁴CO-, R⁵OCO- or R⁶SCO-

wherein R⁴ is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl, aralkyl or aryl and R⁵ and R⁶ are alkyl or aralkyl. 3. Verbindungen nach Anspruch 1 oder 2 aus der Gruppe der folgenden:

N⁴-Acetyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-propionylcytidin,
N⁴-Butyryl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-isobutyrylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylbutyryl)cytidin,
5′-Deoxy-N⁴-(2-äthylbutyryl)-5-fluorcytidin
5′-Deoxy-N⁴-(3,3-dimethylbutyryl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-pivaloylcytidin,
5′-Deoxy-5-fluor-N⁴-valerylcytidin,
5′-Deoxy-5-fluor-N⁴-isovalerylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methylvaleryl)cytidin,
5′-Deoxy-5-fluor-N⁴-hexanoylcytidin,
5′-Deoxy-5-fluor-N⁴-heptanoylcytidin,
5′-Deoxy-5-fluor-N⁴-octanoylcytidin,
5′-Deoxy-5-fluor-N⁴-nonanoylcytidin,
5′-Deoxy-5-fluor-N⁴-hexadecanoylcytidin,
N⁴-Benzoyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-methylbenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-methylbenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(2-methylbenzoyl)cytidin,
5′-Deoxy-N⁴-(4-äthylbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,4-dimethylbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dimethylbenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(3,4-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(3,4,5-trimethoxybenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3,4,5-triäthoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(4-äthoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-propoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(3,5-diäthoxybenzoyl)-5-fluorcytidin,
N⁴-(4-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-N⁴-(3,4-dichlorbenzoyl)-5-fluorcytidin,
5′-Deoxy-N⁴-(3,5-dichlorbenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(4-nitrobenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxycarbonylbenzoyl)cytidin,
N⁴-(4-Acetylbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(phenylacetyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(4-methoxyphenylacetyl)cytidin,
5′-Deoxy-5-fluor-N⁴-nicotinoylcytidin,
5′-Deoxy-5-fluor-N⁴-isonicotinoylcytidin,
5′-Deoxy-5-fluor-N⁴-picolinoylcytidin,
5′-Deoxy-5-fluor-N⁴-(2-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(5-nitro-2-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(2-thenoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(5-methyl-2-thenoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(1-methyl-2-pyrrolcarbonyl)­cytidin,
5′-Deoxy-5-fluor-N⁴-(3-indolylacetyl)cytidin,
N⁴-(3-Butenoyl)-5′-deoxy-5-fluorcytidin,
3′-O-Benzoyl-5′-deoxy-5-fluorcytidin,
N⁴,3′-O-Dibenzoyl-5′-deoxy-5-fluorcytidin und
5′-Deoxy-N⁴-(äthylthio)carbonyl-5-fluorcytidin.
3. Compounds according to claim 1 or 2 from the group of the following:

N⁴-acetyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-propionylcytidine,
N⁴-butyryl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-isobutyrylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylbutyryl) cytidine,
5'-deoxy-N⁴- (2-ethylbutyryl) -5-fluorocytidine
5′-deoxy-N⁴- (3,3-dimethylbutyryl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-pivaloylcytidine,
5′-deoxy-5-fluoro-N⁴-valerylcytidine,
5′-deoxy-5-fluoro-N⁴-isovalerylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methylvaleryl) cytidine,
5′-deoxy-5-fluoro-N⁴-hexanoylcytidine,
5′-deoxy-5-fluoro-N⁴-heptanoylcytidine,
5′-deoxy-5-fluoro-N⁴-octanoylcytidine,
5′-deoxy-5-fluoro-N⁴-nonanoylcytidine,
5′-deoxy-5-fluoro-N⁴-hexadecanoylcytidine,
N⁴-benzoyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-methylbenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-methylbenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (2-methylbenzoyl) cytidine,
5′-deoxy-N⁴- (4-ethylbenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,4-dimethylbenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dimethylbenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxybenzoyl) cytidine,
5′-deoxy-N⁴- (3,4-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (3,4,5-trimethoxybenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3,4,5-triethoxybenzoyl) cytidine,
5′-deoxy-N⁴- (4-ethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-propoxybenzoyl) cytidine,
5′-deoxy-N⁴- (3,5-diethoxybenzoyl) -5-fluorocytidine,
N⁴- (4-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-N⁴- (3,4-dichlorobenzoyl) -5-fluorocytidine,
5′-deoxy-N⁴- (3,5-dichlorobenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (4-nitrobenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxycarbonylbenzoyl) cytidine,
N⁴- (4-acetylbenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (phenylacetyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (4-methoxyphenylacetyl) cytidine,
5′-deoxy-5-fluoro-N⁴-nicotinoylcytidine,
5′-deoxy-5-fluoro-N⁴-isonicotinoylcytidine,
5′-deoxy-5-fluoro-N⁴-picolinoylcytidine,
5′-deoxy-5-fluoro-N⁴- (2-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (5-nitro-2-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (2-thenoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (5-methyl-2-thenoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (1-methyl-2-pyrrolcarbonyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-indolylacetyl) cytidine,
N⁴- (3-butenoyl) -5′-deoxy-5-fluorocytidine,
3′-O-benzoyl-5′-deoxy-5-fluorocytidine,
N⁴, 3′-O-dibenzoyl-5′-deoxy-5-fluorocytidine and
5'-deoxy-N⁴- (ethylthio) carbonyl-5-fluorocytidine.
4. 5′-Deoxy-5-fluorcytidin-Derivate nach Anspruch 1 oder 2 aus der Gruppe der folgenden:

5′-Deoxy-5-fluor-N⁴-octadecanoylcytidin,
N⁴-Cyclopropancarbonyl-5′-deoxy-5-fluorcytidin,
N⁴-Cyclohexancarbonyl-5′-deoxy-5-fluorcytidin,
N⁴-(1-Adamantancarbonyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(2-methoxybenzoyl)cytidin,
5′-Deoxy-N⁴-(2,4-dimethoxybenzoyl)-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-piperonyloylcytidin,
5′-Deoxy-5-fluor-N⁴-(4-fluorbenzoyl)cytidin,
N⁴-(2-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
N⁴-(3-Chlorbenzoyl)-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(3-nitrobenzoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-[4-(methylthio)benzoyl]cytidin,
5′-Deoxy-5-fluor-N⁴-(2-naphthoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-furoyl)cytidin,
5′-Deoxy-5-fluor-N⁴-(3-phenylpropionyl)cytidin,
N⁴-Cinnamoyl-5′-deoxy-5-fluorcytidin,
2′,3′-di-O-Benzoyl-5′-deoxy-5-fluorcytidin,
N⁴,2′-0,3′-O-Tribenzoyl-5′-deoxy-5-fluorcytidin,
5′-Deoxy-5-fluor-N⁴-(octyloxycarbonyl)cytidin,
N⁴-(Benzyloxycarbonyl)-5′-deoxy-5-fluorcytidin und
5′-Deoxy-5-fluor-N⁴-formylcytidin.
4. 5'-deoxy-5-fluorocytidine derivatives according to claim 1 or 2 from the group of the following:

5′-deoxy-5-fluoro-N⁴-octadecanoylcytidine,
N⁴-cyclopropanecarbonyl-5'-deoxy-5-fluorocytidine,
N⁴-cyclohexanecarbonyl-5'-deoxy-5-fluorocytidine,
N⁴- (1-adamantane carbonyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (2-methoxybenzoyl) cytidine,
5′-deoxy-N⁴- (2,4-dimethoxybenzoyl) -5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴-piperonyloylcytidine,
5′-deoxy-5-fluoro-N⁴- (4-fluorobenzoyl) cytidine,
N⁴- (2-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
N⁴- (3-chlorobenzoyl) -5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (3-nitrobenzoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- [4- (methylthio) benzoyl] cytidine,
5′-deoxy-5-fluoro-N⁴- (2-naphthoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-furoyl) cytidine,
5′-deoxy-5-fluoro-N⁴- (3-phenylpropionyl) cytidine,
N⁴-cinnamoyl-5′-deoxy-5-fluorocytidine,
2 ′, 3′-di-O-benzoyl-5′-deoxy-5-fluorocytidine,
N⁴, 2′-0.3′-O-tribenzoyl-5′-deoxy-5-fluorocytidine,
5′-deoxy-5-fluoro-N⁴- (octyloxycarbonyl) cytidine,
N⁴- (benzyloxycarbonyl) -5'-deoxy-5-fluorocytidine and
5'-deoxy-5-fluoro-N⁴-formylcytidine.
5. Die Verbindungen gemäss den Ansprüchen 1-4 zur Verwen­dung als Heilmittel, insbesondere als Antitumormittel.5. The compounds according to claims 1-4 for use as medicines, in particular as anti-tumor agents. 6. Verfahren zur Herstellung der Verbindungen nach einem der Ansprüche 1-4, dadurch gekennzeichnet, dass man eine Verbindung der allgemeinen Formel
Figure imgb0016
 worin R⁷ Wasserstoff oder eine Aminoschutzgruppe, R⁸ und R⁹ unabhängig voneinander Wasserstoff oder eine Hydroxyschutzgruppe oder R⁸ und R⁹ zusammen eine cyclische Hydroxyschutzgruppe sind, mit einer Verbindung der allgemeinen Formel XCOR⁴, worin X eine Abgangsgruppe und R⁴ Wasserstoff, Alkyl, Cycloalkyl, Oxoalkyl, Alkenyl¸ Aralkyl oder Aryl ist, oder mit einer Verbindung der allgemeinen Formel YCOR¹⁰, worin Y Halogen und R¹⁰ eine Gruppe der Formel R⁵O- oder R⁶S-, in der R⁵ und R⁶ Alkyl oder Aralkyl sind, umsetzt und eine vorhandene Schutzgruppe abspaltet.6. A process for the preparation of the compounds according to any one of claims 1-4, characterized in that a compound of the general formula
Figure imgb0016
 wherein R⁷ is hydrogen or an amino protecting group, R⁸ and R⁹ are independently hydrogen or a hydroxy protecting group or R⁸ and R⁹ together are a cyclic hydroxy protecting group, with a compound of the general formula XCOR⁴, wherein X is a leaving group and R⁴ is hydrogen, alkyl, cycloalkyl, oxoalkyl, alkenyl¸ Aralkyl or aryl, or with a compound of the general formula YCOR¹⁰, wherein Y is halogen and R¹⁰ is a group of the formula R⁵O- or R⁶S-, in which R⁵ and R⁶ are alkyl or aralkyl, and an existing protective group is split off. 7. Pharmazeutische, insbesondere antitumor-wirksame Präparate auf der Basis einer Verbindung nach einem der Ansprüche 1-4.7. Pharmaceutical, in particular antitumor-active preparations based on a compound according to any one of claims 1-4. 8. Verwendung einer Verbindung nach einem der Ansprüche 1-4 zur Herstellung von Arzneimitteln zur Behandlung von Tumoren.8. Use of a compound according to any one of claims 1-4 for the manufacture of medicaments for the treatment of tumors.
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EP0602454A1 (en) * 1992-12-18 1994-06-22 F. Hoffmann-La Roche Ag N-Oxycarbonyl substituted 5'-deoxy-5-fluorocytidines
WO1995021183A1 (en) * 1994-02-02 1995-08-10 Acid (Canada) Inc. Halogenated derivatives of 2,3'-o-cyclocytidine compounds and process for production thereof
EP0698611A1 (en) * 1994-08-26 1996-02-28 F. Hoffmann-La Roche Ag Process for N-acyl-5-fluorocytidine derivatives
FR2763953A1 (en) * 1997-06-02 1998-12-04 Hoffmann La Roche 5'-DESOXY-CYTIDINE DERIVATIVES
EP0882734A2 (en) * 1997-06-02 1998-12-09 F. Hoffmann-La Roche Ag 5'-Deoxy-cytidine derivatives
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WO1995021183A1 (en) * 1994-02-02 1995-08-10 Acid (Canada) Inc. Halogenated derivatives of 2,3'-o-cyclocytidine compounds and process for production thereof
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FR2763953A1 (en) * 1997-06-02 1998-12-04 Hoffmann La Roche 5'-DESOXY-CYTIDINE DERIVATIVES
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US6211166B1 (en) * 1997-06-02 2001-04-03 Hoffman-La Roche Inc. 5′-deoxy-cytidine derivative administration to treat solid tumors
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WO2005063786A3 (en) * 2003-12-22 2006-12-14 Hoffmann La Roche Process for fluorocytidine derivatives
US7745475B2 (en) 2004-06-05 2010-06-29 Astrazeneca Ab Heteroaryl benzamide derivatives as GLK activators
US7700640B2 (en) 2004-10-16 2010-04-20 Astrazeneca Ab Process for making phenoxy benzamide compounds
US7943607B2 (en) 2005-05-27 2011-05-17 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
US7842694B2 (en) 2005-07-09 2010-11-30 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
US7642263B2 (en) 2005-07-09 2010-01-05 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
US7642259B2 (en) 2005-07-09 2010-01-05 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
US7977328B2 (en) 2005-07-09 2011-07-12 Astrazeneca Ab Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes
US7973178B2 (en) 2005-11-28 2011-07-05 Astrazeneca Ab Chemical process for the preparation of an amido-phenoxybenzoic acid compound
US7902200B2 (en) 2006-10-23 2011-03-08 Astrazeneca Ab Chemical compounds
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US7696191B2 (en) 2006-12-21 2010-04-13 Astrazeneca Ab Crystalline compound
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